Journal
JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY
Volume 30, Issue 8, Pages 1317-1324Publisher
WILEY-BLACKWELL
DOI: 10.1111/jgh.12931
Keywords
hepatocellular carcinoma; radiotherapy; sensitization; Sonic Hedgehog
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Funding
- National Science Council, Execute Yuan [NSC 101-2314-B-002-148-MY2, MOST 103-2314-B-002-188-MY2]
- National Taiwan University Hospital [NTUH 100N1721, 101N2007, 102N2303]
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Background and AimSonic Hedgehog (SHH) is a regulator in tumorigenesis of hepatocellular carcinoma (HCC). This study aimed to determine whether radiation-induced SHH signaling occurs in HCC and whether SHH inhibitor acts as a radiosensitizer. MethodsThe in vitro effects of combining SHH ligand (recombinant human SHH) or inhibitor (cyclopamine) with irradiation were evaluated in the human HCC cell lines, Huh-7 and PLC/PRF/5, and murine cell line BNL. Cell survival and apoptosis were measured using a colony formation assay, annexin-V staining, and poly (ADP-ribose) polymerase activation. Western blotting and immunofluorescence staining were used to detect protein expression. The in vivo response to radiotherapy and/or cyclopamine was tested in BALB/c mice bearing an orthotopic allogeneic tumor. ResultsTreatment of HCC cells with irradiation and SHH ligand had a protective effect on clonogenic cell survival. Treatment with irradiation and cyclopamine was a more potent inhibitor of cell proliferation than either modality alone. The antiproliferative activity of cyclopamine was attributable to apoptosis induction. Radiation dose-dependently upregulated the expression of Gli-1 (a transcription factor induced by SHH), and this effect was observed mainly in the nucleus. When combined with cyclopamine, irradiation inhibited Gli-1 and increased DNA double-strand breakage. Radiotherapy increased SHH and Gli-1 expression in allogeneic tumor. When compared with radiotherapy alone, cyclopamine with radiotherapy reduced the mean tumor size of orthotopic tumors by 67% (P<0.05). ConclusionCombining an SHH inhibitor with radiotherapy may enhance HCC cell and orthotopic tumor radiosensitivity.
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